For today's episode, Dr. Richard Frey returns
to share some updates with his research and clinical
work. Dr. Frey is an MD, board certified in pediatrics,
neurology with special competence in child neurology,
and is a certified principal investigator. In
addition, Dr. Frey is a PhD in physiology and
biophysics. This episode is all about Luke O
'Boren. Dr. Fry shares many great routes to learning
more about leukoborne, including his upcoming
book, Folate Fix, and two websites, Neurological
Health Foundation and Healthy Child Guide. Please
see the show notes for links to all of these
wonderful resources. But first, a message about
daylight computer and chroma. I would like to
take a moment and mention a pressing issue we
are seeing in our modern world and that is tech
use and tech light. The data are impressive and
concerning on isolated wavelengths of light,
especially shorter wavelengths, which is blue
light. For those that don't know, We have chromophores,
which are special proteins that absorbs specific
wavelengths of light. For blue light, the light
that is LED light and tech light, that protein
is called melanopsin. Melanopsin is responsible
for our circadian biology, physiology, and cell
functioning. hormone regulation, and even a connection
to an area huge for mood. A consideration we
should include is this protein was not even discovered
until 1998. It seems important for us to understand
how our biology uses the different wavelengths
of light. for various aspects of our biology.
This blue light chromophore is our master controller,
our master clock. Remember circadian rhythm is
a two -part process, two independent parts, light
and dark. For a quick reference, see the 2017
Nobel Prize in Physiology and medicine. But for
now, I have something exciting. I want to introduce
a product unlike any other product available.
A highlight is the product from Daylight Computer
Company created their product based on these
factors. The Daylight Computer is completely
blue light free. It has no flicker, short wavelength
flicker. is extremely harmful for our eyes and
downstream biology. Light flicker is constantly
turning our central nervous system on and off.
Essentially it is like going to a light switch
and repeatedly turning it on and off. The problem
is blue light and LED light does this and it
is so rapid You cannot even perceive this in
real time. The daylight computer is the lowest
stimulation and foremost for sensory sensitive
users. It is no question that the alternative
product, especially when used at night, do not
address or consider this in their product. It
is so toxic to human biology. Big tech corporations
have patents on how their short wavelength implicate
the human nervous system. And a bonus, despite
daylight computer not having backlight, it is
very functional for outdoor use. And of course,
increased sunlight is always preferred. I am
happy to offer a discount for the Daylight Computer.
You can use the code Autism for a $25 off coupon.
Again, use the code Autism and the discount code
for $25 off. See the link in the show notes to
Daylight Computer Company or just give it a quick
search in your internet browser. Use the code
Autism. for $25 off. I would like to mention
Chroma, lights designed for humans. Chroma, a
Seattle -based innovator founded by ex -NASA
and Air Force engineer Michael Shapiro, is on
a mission to enhance physical and mental health
with purpose -built devices, unlocking peak human
health. cognitive function and performance. Shapiro
launched Chroma to restore the natural light
lost to screens in indoor living and delivers
faster recovery, sharper minds and better sleep.
Their products hit hard. The Iron Forge speeds
muscle repair with red and near -infrared light,
while the Skylight mimics sunlight. to boost
sleep and energy. A standout, the Forge Lamp,
is a portable gem that fires 660 nanometer and
850 nanometer light to energize mitochondria
and heal tissues on the go. Remember the four
red light chromophores on cytochrome c -oxidase
frequently talked about in the podcast. This
is why. Their products are built with military
-grade durability that have lasting impact. Chromis
Tech fuses precision and power. Gallium titride
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Every design decision Chroma makes serves a purpose
to create devices that are precise, durable,
and effective for improving human life. Remember,
humans use different wavelengths of light for
different functions of life. Remember when I
ask, what do you think light is? Chroma designs
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lights and blue light blocking glasses. They
are US made and Chroma ships globally and accepts
FSA and HSA. payments. Use autism at checkout
for a 10 % off discount. That's autism at checkout
for a 10 % off discount. Dr. Frey, thank you
for joining again. I'm super excited about this
and the recent news with Lickle Warren. Yeah,
thank you so much for inviting me. I'm glad that
there's some interest in this. We've had a lot
of success, and I hope that other people can
have the same success. Yeah, yeah. This is a
great opportunity, I think. Lookalore, it seems
like it might be one of those low -risk, high
-reward type of things as well, meaning if somebody
uses it and if it doesn't work, then there's
not a really bad side effect. Is that pretty
accurate? Yeah. I mean, so it's a type of folate,
and we know folates are pretty safe long term.
They're natural vitamins. And one of the great
things about B vitamins, so folate is vitamin
B9. And so the B vitamins in general are what
we call water soluble. which means you pee them
out at the end of the day. So your body has a
natural mechanism for controlling, you know,
how much you have. So, you know, so that's really
good. And so the worst thing you do, what we
say is the worst thing you do is make expensive
pee. Okay. Okay. I've heard that with like bodybuilders
and people would take vitamins and supplements
and so forth. Some people will just say it's
just expensive pee and so forth. So I like that.
No, it's kind of like a Intranasal oxytocin is
kind of like that too with autism But it doesn't
have great success and it seems like the look
of Warren has better success Can you just start
with how? You discover look of Warren as a possible
treatment option for autism Sure, you know, I'll
briefly kind of tell you guys that the story
you know, of the discovery kind of of of leukovorin
as a treatment because it's kind of interesting.
So what we know, not to start out technical,
but what we can see here is a brain and this
was of course we know is important. This controls
how we think and how we move, but to get into
the brain everything that goes into the brain
has to be actually selected to go in there because
the brain is a very, very controlled environment.
So we have this thing called the blood -brain
barrier. When you have your blood over here,
these are your red cells, going through your
vessels, things can't just go into the brain.
There's this barrier here that selects all the
molecules that actually go in there. And so that's
a good and bad thing, right? You know, that if
you don't get things in there that are not supposed
to be in there, but the other side of it is that
you have to have these special carriers to bring
things into the brain. If they weren't working,
you know, that's a problem. You know, you don't
get what you need into the brain. So one of the
things that we know that is really important
is folate. Okay, and many people think of folate
five, methyl tetrahydrofolate is kind of our
main folate in our body. And so that has to be
brought into the brain. And there's really specialized
mechanisms. You know, the body is very complex.
So there's this thing called the folate receptor
alpha, which you can see here. And here's the
blood vessel here. And here's the brain, the
cerebral spinal fluid. And so this receptor,
actually binds onto folate and it pulls it across
and dumps it into the brain. And this is really
important because the amount of folate in the
brain, the concentration, is two to three times
higher than it is in the blood. So this is actually
doing work and pulling folate into the brain
and dumping it from the vessels into the brain.
in doing a lot of work. There's other ways of
getting folate into the brain. We have something
called the reduced folate carrier over here,
but you can see that it's smaller than the folate
receptor alpha, and there's a reason for it.
It just doesn't like folate as much. You know,
you could think of the folate receptor alpha
as kind of a fire hose and the reduced folate
carrier as a straw. So we really want this to
work. Well, so we know folate is really, really,
really important. And so really folate is one
of the most important vitamins for a number of
different reasons. We have something called the
folate cycle, which is here. And it does a number
of things. It processes folate in a number of
ways for the body. You know, first you have the
stuff on the left -hand side, and that is where
folate makes something called purines. And those
are the building blocks of certain genetic material,
RNA and DNA. So we know if you don't have folate,
you're not going to make RNA and DNA well, and
that's our genetic code. so you actually can
get genetic abnormalities if you don't have folate
available. Folate is also important for making
something called BH4, or tetrahydrobiopterin,
and that's really important for making neurotransmitters,
serotonin, melatonin, dopamine, norepinephrine,
and for nitric oxide production. And there's
a really interesting phenomenon with BH4 and
why it's so important. And that is for nitric
oxide, we've heard good and bad things about
nitric oxide. Some people say it's toxic, some
people say it's good. Well, for the most part,
it's a good molecule in our body. But one of
the things that happens is if you don't have
BH4, when it's being made, instead of making
nitric oxide, you actually make a toxic molecule
called a p -oxynitrate. So the same pathway that
produces nitric oxide, when you don't have BH4,
which it needs for nitric oxide production, it
ends up it doesn't stop. It keeps trying to make
nitric oxide, but if you don't have BH4, it actually
makes a toxic molecule. So BH4 is extremely important.
And then it's important for something called
ATP, which is important for the mitochondria,
the powerhouse of our cell to make energy. And
ATP is the energy currency of ourselves. On the
other side is what a lot of people talk about
is methylation. And so on the other side of the
folate cycle, you have methylation, where you
use B12 and folate. to make methyl groups, and
those are important molecules that regulate if
DNA is turned on and off. So that's really important,
right? Every cell in your body has the same DNA.
So how do the cells work differently? Well, it's
because in certain cells the DNA is turned on
or off, and that's all due to methylation. So
if methylation isn't working, you're in trouble.
And it ends up that this then goes into what
we call redox metabolism or trans -sulfuration
to make glutathione, which is your major antioxidant
of your body. So you can see folate is really
central to all of these different things. Some
of the nuances here is that we have the MTHFR.
And a lot of people like to talk about the polymorphisms,
that is small changes that make it make it more
or less efficient. And so it may be more or less
efficient at making 5 -methyltetrahydrofolate,
which we think of as our main folate. And then
that will interfere with methylation. But you
also have to realize that we need folate over
here. This is 5 -10 -formaline folate. That's
what leukovorin comes in. And that goes to this
other side. So it's a very complex pathway. The
great thing about leukovorin and folinic acid
is that the gut actually turns half of what's
made of leukovorin when you take it orally to
five -method tetrahydrofolate. So you actually
have folate come in here and over here. So you
kind of bypass the MTHFR, which is a good thing
if it's not working all that well. The other
really important thing, concept in folate, is
that folic acid, which we all know of, we think
that that's our great type of folate, is a synthetic
form of folate. It's not natural. So our body
can't use it naturally. And it has to go through
something called the dihydrofolate reductase
enzyme to change it from... folic acid into tetrahydrofolate
for it to be used. And there's two problems there.
One, some people have changes in the dihydrofolate
reductase enzyme that makes it less efficient.
And two, we only have so many of these. So the
idea of giving more folic acid, right, you want
to get more folate in the body, you say, I'll
just give more folic acid. But you can't do that.
because there's a limitation here, right? There's
a bottleneck because you only have so much of
this enzyme, so you only can change so much folic
acid into tetrahydrofolate. So these are just
some of the nuances of folate to think about.
So sorry to go on. No, that's fine. I was going
to ask you about BH4. I had it on my notes here.
I'm glad you brought it up. Did you have other
questions or? No, I just, um, I ran into it,
um, covering, um, the womb and like the development
process of the womb and like the timing and so
forth. And I ran into VH4 and I was connected
to intellectual disabilities and motor movements,
especially gross motor and things like seizures.
And I was just like, I bet this is involved.
But you confirmed that, so. Yeah, the major disorders
that of lack of BH4, usually a person looks like
a Parkinson patient. So the syndromes called
Sagawa syndrome or dopamine response of dystonia.
The major symptoms you see is more like a Parkinson's
patient, but there's other things too, because
it's not only dopamine that you've lost, you've
lost serotonin and norepinephrine. It's really,
really important. Yeah. With the placenta and
neurogenesis, I found that it was important with
that fetal ATP that you show. Yeah, so it's very
important. It's a hard molecule to study because
it's a fleeting molecule. It's not very stable.
And then it's very expensive as a supplement.
We used to be able to get some from Switzerland,
but I don't think they make it anymore. And so
now, that's where I originally started, was studying
BH4. And there's a medicine called KuVan, which
is synthetic BH4. And it's made for a rare type
of phenylalanemia. And since it's a rare disease,
it's extremely expensive. So it's not a practical
thing to use. But in our studies, we show that
it does help somewhat. But folate helps a lot
more. OK, yeah, yeah. To get back to the cerebral
folate deficiency story, we have to thank Dr.
Vincent Raymakers. He's a pediatric neurologist
from Belgium and he was working in Germany at
that time. He was seeing all these patients that
had neurodevelopmental disorders and he couldn't
figure out what was going on with them, why they
had the disorders. worked them up. And then he
teamed up with Dr. Blau, who's in Zurich, Switzerland.
And Dr. Blau is probably the most world renowned
scientist on the neurochemistry of the brain.
And so what he would do is he sent samples of
cerebral spinal fluid so he did some LPs this
is what happens if we can't figure it out we
try to do everything and one of them is to take
some fluid from the CSF the fluid that surrounds
the brain and analyze it and say is there something
there or something not there and they discovered
that these patients had very low folate in their
brain and so this is kind of a new discovery.
And you can see that he studied these children
over time. And what was interesting is when he
looked at some folate levels, they actually dropped
over time in some of these kids. So one of the
things that he did was he wanted to know why
this was. So he knew that the folate receptor
alpha was the major transport mechanism. So of
course he said, oh, this must be a genetic problem.
with the folate receptor alpha. So he sequenced
the gene, but he couldn't find any abnormalities.
And, and so he said, you know, it's kind of scratchy
sentence, huh? So then what happened is he teamed
up at the same time. It's an interesting story.
At the same time, Dr. Quatro's at SUNY downstate
in Brooklyn, New York, was looking at folate,
but for birth defects. And trying to figure out
why, you know, we didn't get folate into the
baby and they caused birth defects. And what
he discovered, at the same time he was looking
at birth defects, and he discovered that in these
transport mechanisms, that there were these two
antibodies running around people's bloods. Usually,
antibodies attack viruses and bacteria to protect
us. But some people have antibodies to themselves,
to their own body, and so -called autoimmune
diseases. So he found that there was these antibodies
that bound to this folate receptor alpha here
and stopped it from working. So he was looking
at birth defects and And Dr. Rainmaker's found
these patients. So Dr. Rainmaker said, well,
why don't we test these kiddos for these antibodies?
And so then they published their findings, really,
in a really nice paper in the New England Journal
of Medicine, probably the best journal in the
world, to describe this new phenomenon called
cerebral folate deficiency. And they found that
these kiddos had particular symptoms. Starting
usually before year olds, they'd have decreasing
head growth, so their brain stopped growing,
so their head stopped growing. They'd have neurodevelopmental
regressions, so they'd lose skills that they
had. They'd have dyskinesias, which are movement
disorders. Some of them had epilepsy. And then
some of them had what we call periminal signs,
which looks like cerebral palsy. And if they
weren't treated, they went on to have visual
disturbances and hearing loss. So these kids,
they measured this antibody, this folate receptor
antibody, and looked at the titers. And we can
see that the mean titers in the patients with
cerebral folate deficiency were all the way up
here. where the control subjects were down here.
So the question was, OK, well, how do we treat
this? Well, they had also used leukovorin. So
that's what we'll talk about a little bit. And
the thing about leukovorin is some of it gets
turned into 5 -methy tetrahydrofolate. But leukovorin
is a reduced folate like 5 -methy tetrahydrofolate.
and it can go through this reduced folate carrier
and get and go into the brain. Now of course
it's not that easy remember I said that reduced
folate carrier is like a straw and the levels
in the brain are two to three times out of the
blood normally. So what you have to do is get
high doses of folate in the blood and push it
through the straw to the other side. And so some
of the science that we looked at is, okay, we
know that we have these folate antibodies. Do
they correlate with levels of folate in the cerebral
spinal fluid? So that's a question people ask.
How do you know that they really are doing something?
So this is a study by Dr. Rainmakers where he
showed that the blocking antibody correlated
with levels of. folate in the CSF, so we know
that correlates. And this is a study we did on
autism where we found that there was a correlation.
Although in autism it's very interesting, we
didn't find any of them were below the normal
limit. We found a lot of them were low normal
but not below the normal limit. And so there's
some subtleties in autism that we think are driving
many things. So as more so they first described
this These patients in the New England Journal
of Medicine and then other papers started to
be Published and so this one was cerebral folate
deficiency with autism and the response to phalamic
acid You know, so they show that you can use
phalamic acid to improve symptoms, and they described
an individual with autism. So, and then another
report came along of autistic symptoms, developmental
regression, mental retardation, epilepsy, and
dyskinesia in full deficiency. But again, started,
we started to realize that, oh, there's patients,
one of the phenotypes of this is autism. And
so, and here's another one where they found low
functioning kids. with autism had a cerebral
folate deficiency. And this is an interesting,
in one of their studies, they looked at the folate
antibody titer and they looked at aggressive
behavior. And you can see that aggressive behavior
matches the titer almost exactly. Wow. So then,
of course, we wanted to know more about treatment.
So this is a paper that Dr. Rainmakers did to
show if you start treatment, how many people
recover from these different symptoms. And things
like periminal tract defects, motor problems,
unsteadiness, very much dyskinesia, so -so. and
he found that autism and intellectual disability
not so much. You really had to start early in
treatment. So then they also linked cerebral
folate deficiency to mitochondrial disorders.
Because you remember, I said the folate receptor
alpha has to essentially pull folate into the
nervous system. So it takes energy. And so if
the mitochondria isn't working, it's not gonna
work. But this is an outstanding study because
what Dr. Rainmaker showed was this is the patient
that started when they were diagnosed and the
left. And so these are MRIs and you don't have
to be a neuroradiologist to see that there's
a really bad MRI because all this white stuff
does not belong there. So that's loss of white
matter. the wires that are in the brain. So it
looks very severe and you can see almost these
holes inside the thalamus and basal ganglias.
So most of the time we would say, oh, this is
not a recoverable brain. But after three years
of treatment with some mitochondrial supplements
and leukovorin, the brain is almost back to normal.
Wow. So that's pretty impressive. So going on
with the mitochondrial disease, then another
paper came out where they found that there was
a whole slew of patients with mitochondrial disease
that had cerebral folate deficiency. So, you
know, the story started building. So what happened
is, you know, myself and so this is about 2008.
And so and this is when I was just starting to
really treat kids with autism. And so I was working
with Dr. Rossignol. We were working on some review
papers and we said, well, kids with autism have
mitochondrial problems. You know, they have immune
problems. How many of these kids are running
around our clinic with this folate receptor antibody?
He said, you know, we can measure it. We could
send it to Dr. Quatros. And so what we did is
we systematically offered the test to our patients
when they came in. And we made an interesting
discovery which we published in 2012 in molecular
psychiatry of the cerebral folate antibodies
in autism. And what we discovered was that of
the blocking antibody, 60 % of the kiddos had
the blocking antibody and 50 % had the binding
antibody. So it wasn't subtle. And if you ask
how many had either antibody, 75 % had at least
one or two antibodies. So that's a lot of kids
with autism. And so, you know, of course we didn't
have controls to see if it was, you know, higher
than control. So Dr. Ray Maker had another study
where he compared the percentage of kids with
autism with the antibodies to controls, which
were developmentally delayed controls without
autism. And we can see in his study, 47 % of
them had the antibody, only 3 % of the kids with
developmental delays, but no autism had the antibodies.
That really discriminates the autism out of it.
It extracts it out. And so then another study
was done by at the NIH by Susan Suito with measure
using LPs to measure, you know, folate in the
CSF of kids with autism. And so what she found
is that if you measure the kids that have frankly
low CSF levels, it's 18%. So at least 18 % have
frankly low levels of folates are below normal.
But if you remember, when I showed you that other
diagram, I said in our study, we found that these
kids had kind of more low normal. So this doesn't
even kids the kids that are low normal. So those
that have clearly defined cerebral folate deficiency
is 18%, which is a big number, you know, that's,
you know, a fifth of kids with autism, you know.
So, so one of the things we said is, well, If
the kids have the antibody, do you think that
they will respond to treatment? We knew about
leukovorin. So what we did is the kids that were
positive, 44 of them, we treated with leukovorin,
two milligrams per kilogram. And this was open
label, so they knew they were getting it. And
then we compare them to something called a weightless
control group. And these were kiddos. that were
essentially waiting for results. And neither
of them made any other changes. And when they
came back to the clinic, we asked them to rate
whether things got better or worse on several
different aspects. But the most important ones
were language and behavior. And what we found
is that in all the language measures, receptive
language, expressive language, and verbal communication,
there was improvement. So higher up is improvement.
So you can see the black dots are the ones that
were treated. So you could just see, you don't
even need statistics to see that there's more
black dots above the line here than there are
clear dots. We also found that improved stereotype
behavior. attention and if you look at who improved
you say those that improved in receptive language
about 66 percent 67 percent improved in expressive
language receptive language and verbal communication
in about a little less 40 percent improved on
verbal communication but attention improved in
about 60 percent mood about 50 % stereotype behavior
about 50 % so it wasn't everybody but it's a
substantial number so then you know so we said
wow this is really interesting and a potential
treatment but of course what we did first was
something called an open label study and open
label study means people know that they're getting
the drugs so they're biased right they say oh
yeah this this thing worked yeah I love this
so we had to do the double blind placebo control
study. And at this time, I was at when we did
this study, we were I was at UT Houston. And
they just got recruited to Arkansas Children's
Hospital to lead their autism program. So I said,
Well, the first thing I'm going to do is do a
controlled study on leukovorin. And that study
was published in 2016. And what we did is we
randomized kids, 48 kids, to either see if you
see a placebo or leucovorin. At that time, we
were calling it high -dose folinic acid. We don't
like using folinic acid anymore because so many
people confuse it with folic acid. So we've kind
of changed just saying leucovorin, so there's
no confusion. But it's essentially the same molecule.
And so in the first, in our open -label study,
we found that language was improving. So that
was a great thing because what we could do is,
you know, many problems that we have in studies
of autism is that there isn't objective measures
of improvement. Many of them are parent questionnaires
or, you know, what does the physician think is
better or is it not better, you know. But for
language, you have very sophisticated measurement
tools that can measure many aspects of language.
And you can have somebody, a trained person,
to actually do the measurement. And they don't
know whether the child is on the medication or
not. So we can actually put numbers to it. And
so what we found is that you can see here in
12 weeks, the ones that were in leucovore and
ephelinic acid, their verbal communication increased
dramatically compared to those that were on placebo
and of course they were getting speech therapy
and everything so they improved a little bit
but you can see the difference here was dramatic.
And then we asked a question because in this
one we had all comers those that were positive
and negative for the for the folate autoantibody
and so we asked does it matter if you're positive
or negative and we found that in fact it did
and if you were positive for the folate autoantibody.
If you had flenic acid or leukovorin, it was
a 77 % response rate. And there's an important
number called number needed to treat. So that's
how many patients you have to treat to get one.
And most people, right, you go to the doctor
and you think that number should be one, right?
You go to the doctor, they give you a drug, you're
all better. So people will be survived surprised
to find out in most clinical trials that number
is anywhere from six to eight So you have to
trade most medications. You have to treat six
people just to get the effect that you want So
a number of one point eight is very good and
this is looking at a response criteria of you
know a very Significant response to phallitic
acid. Of course, there's other kids that have
more of a lackluster response that are slower
So this is pretty good. Now, what we did is we
were able to equate it to how many hours of speech
therapy this equals. It was 177 hours. So that
would be three hours a week for a year, or about
$7 ,000 worth of speech therapy for $300 worth
of a drug. and you know it's not only important
not trying to you know put down speech therapy
but the fact is you know we were talking about
this language is so so so important and the inability
to communicate causes so many problems in children
trying to recover and learn so it's just the
fact if you can get them faster to the place
they need to be they'll be in a lot better shape
yeah and even even i think um the lack of language
The inability to convey their needs is a big
path for self -injurious behavior. I think that's
what I do because they get frustrated. You're
absolutely right. And that's what we're learning,
right? With the spellers and such that there's
stuff in there. Yeah, you can't get it out. And
so it's very frustrating for them. So, you know,
they can't tell you what they want to say. headbanging
and stuff. So that's why language is so important.
Now some people worry about when we start leukovorin,
we get some hyperactivity sometimes in the initial
few weeks. So we said, well, why don't we study
this? Because in our clinical trial, every three
weeks we asked about certain adverse effects
specifically. And although we didn't ask about
hyperactivity, we asked about agitation or excitement.
And we can see at three weeks, those on leukovirin
was about 20%. Those that are on placebo is about
12%. By six weeks, they equaled each other at
about 22%. And at nine weeks, and this is what
we see at long -term that hyperactivity gets
better, see at nine weeks, those on leukovirin
plummeted to zero. Whereas the ones on placebo
continued to have a higher rate. So, you know,
scientifically you say, well, it's no different
than placebo here if you look at statistics,
but, you know, it does tell us that it's pretty
much consistent with what you would see, you
know, kind of in your normal daily routine and
that with leukovorin eventually it does get better.
So then the other really important aspect is
the fact that going back, coming full circle
to Dr. Quatro's research is that these same mechanisms
with the folate autoantibody and the folate receptor
alpha are on the placenta. So the same mechanisms
that takes folate into the brain takes it across
the placenta. And what we find is that a percentage,
about half of the mothers of kids with the folate
autoantibody have it themselves. So that means
they may have had a double whammy. They may have
had a problem getting folate into their body
before birth and then after birth too. And so
to prove this, Dr. Quartros developed an animal
model where he takes, you know, pregnant rats
and injects the folate autoantibody. And these
are all different scales. of different tasks,
passive avoidance, active avoidance, and such,
and the performance on it. And you can see those
that did not have the, that just got a sham did
100%, whereas those that got the antibody either
during gestation and pre -weaning, gestation
or pre -weaning, that they failed on most of
these tasks. And then what he did is he tried
to rescue them. And so, We can see up here that
these are a couple of different tasks. So average
number of calls is essentially language. And
so when the folate autoantibody was given to
the mother here, you can see that the average
number of calls decreased significantly. And
if he gave either dexamethasone, a steroid, or
phalaenic acid, leukovorin, you can see that
all the pups, these are the pups that come out,
they're all rescued in that behavior. And the
same thing on a behavioral task too, as far as
learning. So he showed you can actually rescue
these pups during gestation while they're developing
by giving the mother either high dose folic acid,
leukoborin, or a steroid to decrease the inflammatory
effect of the folate autoantibody. And then he's
done other studies where he showed actually that
the folate autoantibody causes inflammation.
So this is a marker of inflammation, this brown
stuff here. This is the placenta. And so you
can see that there's inflammation when you have
the folate autoantibody. And then he actually
measured folate flux. and also showed that folate
doesn't get into the fetus when you have these
antibodies. One of the other interesting things
that we found, which is a little complex, is
that we saw that kids, we did a study and we
found that the folate autoantibiotic was correlated
with thyroid function. But the thyroid doesn't
have the folate receptor alpha on it. And we
said, huh, how can this be? And what we did is
we actually took fetal tissue and we found that
these brown spots are the folate receptor alpha.
Then we found that up until 17 weeks gestation,
the human thyroid actually does have the folate
receptor alpha. So if your mother has the antibody,
it's actually going to cause abnormalities in
development of the thyroid. So yeah, so that's
a little story of how I got into it in our journey
so far and trying to figure out this mystery
and figure out how to really help kids. That
picture shown of the white matter of those brain
scans was very wild. Yeah, that's very impressive.
Yeah, that was a really good finding. With that
language in the communication, do you think that's
what it's doing, is increasing the white matter
tracks from like Bronecki to Broca? Well, I think,
yeah, I don't, it's, so yes, so there's a study,
there's a nice study I didn't show, where they
actually looked at changes in the brain. in the
white matter with very sophisticated MRI techniques.
And that's what they showed is that the improvement
actually paralleled more development of the white
matter. And so one of the things that we have
to understand that's common about language and
socialization is that they use parts of the brain
that are really far away from each other. They
use the back of the brain and the front of the
brain. And so when the neurons aren't working
well, it's very hard for them to synchronize
those long distances. And if the white matter
isn't in good shape. So those are probably why
we see these symptoms in kids with autism. Because
those particular higher level functioning are
things that really need these. connections from,
from, you know, places in the brain that are
far away from each other. And it may be why we
see some of them have certain splintered skills,
right? Because like mathematics isn't really
just one part of your brain, right? And so that
can overdevelop, whereas the rest of the brain
isn't developed. Yeah. Oh, my gosh, that those
distal connections with that white matter track.
Like maybe the arcuate fasciculus with the language
track, I think, maybe is rescued. Yes, I would
think so, yeah. Wow, that's impressive. Do you
find that the leukovirin helps a certain type
of the autistic phenotype, like the more severe
versus the so -called higher functioning? Or
is it pretty... straight forward across the the
levels we use? Yeah, no, it's a great question.
One thing we do find is that, well, one of our
first studies suggested that the most severe
children are the ones that didn't have language
at all, you know, didn't benefit as much. But,
you know, that's not what I see in some clinical
practice. I see kids that are not talking, start
talking, you know. And so it may be an artifact
of the instruments we're using, because we can
only measure things so far down. So that's the
kind of where the clinical trials don't always
tell you exactly what's going on. You're in a
very controlled setting, an artificial setting,
than the clinical practice. But the one thing
that is really interesting is that We had many
kids some that you know a lot of people are impressed
going from not talking to talking of course But
we found that even kids that were talking and
could have conversations Luke of Orin would improve
their ability to have their higher level, you
know language abilities So the tests that we
use get harder and harder and harder and we can
measure some really sophisticated language abilities
and it seems like they get better and better
understanding and being able to produce things
that are more nuanced as they're treated, even
if they're talking to begin with. Okay, that's
impressive. Brad? You answered my questions about
the utero and the embryo genesis too and the
neural tube. I found that the B9 and folate is
huge for like the neural tube to the crest and
neuralation and so forth. But yeah, you hit on
those time frames and I think... So yeah, so
that's, you know, that's what, you know, we're
trying to move forward as I think I told you
I'm going to have a book coming out called The
Folate Fix. which has about a dozen stories from
parents. So it's not just me, it's a lot of stories
from parents. So you can see what people's journeys
are like and their struggles. And I hope that
will help parents understand things, understand
the struggles that parents go through to get
their kid recovered. So that's one way that we're
trying to get the word out. A lot of physicians
are very interested in how to use it. So part
of that book has kind of a guideline for doing
that. We're hoping to get some learning sessions,
videos up to be more of a training session, more
of a CME course for physicians. And then the
other thing going to what you're talking about
with gestation right now, what we're doing is
we have a grant from the Arizona State to look
at something called transgenerational. aspects
of the folate order antibody, because what we
find is that these run in families. And so this
may be, you know, one of the mysteries with autism
is that there's a very big heritability to it.
And so everybody equates that to genetics, right?
But genetics is only one type of heritability.
And so we're finding these other disorders that
are non genetic, at least not purely genetic,
heritable conditions. And of course, the great
thing is that we can, if we find them, then we
can treat them and we can treat them from the
beginning, you know, before the woman's pregnant,
really, that's, that's where you want to start.
And the man, we find that also that the folate
auto antibody in dad seems to have an effect
too. So, so yeah, so both women and men, you
know, we want to get them prepared. you know,
to become pregnant because, you know, that's
what I try and explain to moms. They have another
child that as soon as you get pregnant, you're
putting a lot of pressure on your body and taking
out all the resources. So you got to build up
those resources to begin with. Yeah, the environment
of the pregnant mother has vastly changed so
much. Um, and I don't want to jump to conclusions
here, but maybe there's a role with like spinal
bifida. Yeah. Oh yeah. Yeah. Most definitely
is. Yeah. Yeah. Yeah. Okay, yeah. Yeah, so that's,
yeah, so that's where Dr. Quattro started out,
you know, so it's kind of funny how things have
kind of come full circle. Yes, yeah, that's so
incredible. Because, wow, how does somebody go
about maybe their autistic, or, as you described,
they're preparing for pregnancy, or they do have
an autistic child, maybe it's a parent, how do
they go about trying to So what I usually suggest
like the basic things is so we have something
called the Neurologic Health Foundation and that's
and some great people on there like Jim Adams
and such and we've put together something called
the Healthy Child Guide. So you can just Google
that the Neurologic Health Foundation Healthy
Child Guide and it's a guide we put together
based on science. of what things you should do
to prepare for and to do during your pregnancy
to keep yourself healthy. The other thing that's
really important is to get a multivitamin that's
very complete and also has reduced folates in
it. So one of the problems with many of the prenatal
vitamins is that since folic acid is the only
thing scientifically that has been shown to reduce
neurotube defects. Many of the manufacturers
won't change to a reduced folate, right? Because
legalistically, you know, it's the only thing,
folic acid is the only thing that's been proven.
We don't have the data on these reduced folates.
But we know that these reduced folates are equivalent
or better, and probably better. Because the other
thing we're finding about folic acid is, you
know, as I was saying, we only have a limited
ability to actually reduce it and make it into
its active form. And so this is kind of one of
the mysteries, right, is that there's a study
that shows that folic acid supplementation prevents
autism, folic acid supplementation during pregnancy,
you know, decreases the risk of autism. But then
when they measure folate levels, mother's broad,
higher folate levels are correlated with greater
risk of autism. So that doesn't quite make sense
on the surface and then you find out that those
greater levels of folate was unmetabolized folic
acid. So that's the problem is that scientifically
too we're finding that folic acid at high levels
will actually inhibit the folate cycle. So when
it gets too high, it can have detrimental effects.
So that's why we can't just give more folic acid.
We have to give what we call reduced folate.
So methotetrahydrofolate, tetrahydrofolate, leucovorin,
and such. So that those go right into the folate
cycle. So we know from experiments that those
type of folates don't inhibit the folate cycle.
So you can give higher doses. Wow, okay. So yeah,
so definitely get a prenatal that has reduced
folates in it. And there's several good ones
that have been made by high quality supplement
companies. Look for the Healthy Child Guide,
you know, and make sure that you plan things
well. Yeah, there's so much that's come out about
that. When could we expect you to book the folate
fix? Probably about a month. Oh, wow. Okay. So
yeah, you can come to my website, autism discovery
.org and sign up for a notice when we get it.
So yeah, you know, fight about things. I spread
that on social media too. And these links and
these organizations that you talked about. Sure.
Yeah, we're on Facebook and TikTok. So if you
want to follow us. You know, follow, like, and
share and all that type of stuff. For my discussions
with you and Nicole, I've learned so much about
how these different things with the folic, versus
the folate, versus the fol... I mean, there's
just so much that's, people, I don't know, it's
hard to discover. Yeah, it's kind of hard to
imagine that vitamins are so complicated. Yeah,
especially the B9. It seems like the B9 is really
complicated. Well, it's important. I think, you
know, there's certain, you know, vitamins like
B9, B12, and such that that are central to so
many different mechanisms that they're so important.
Mm -hmm. Yeah. And when you're deficient, it's
so much goes wrong, you know? Yeah, yeah. Downstream,
it could show up. It manifests as a lot of different
things, I think. Is there anything else that
you would like to share or mention before you
wrap up? Yeah, you know, I mean, I think the
important thing is, you know, this is a great
treatment. You know, I hope people, you know,
find out, tell their doctors about it. You know,
that's where doctors a lot of times find out
about it, about, you know, people bringing them
the research, bring the research papers, you
know, not just a news article because they, you
know. And then, you know, I think always the
important thing, you know, of any of the journeys,
you know, is for parents to know that it's not
a sprint, it's a marathon, and it takes a lot
of work, but you can get there. Yeah. Nicole
mentioned that about the duration of taking these
things, and people will give up on them fast.
Yeah. So it's important to have the guidance
of somebody. I know a lot of parents want to
do things fast. They say, oh, I can get phalamic
acid over the counter. I'm just going to try
it. Oh, I don't want to do the full eight auto
antibody test. But it's kind of important to
do all of these, because it's not that simple.
And you can fail in many different ways. And
you want some type of guidance to know what is
the next step. Many times, we find that Leucovore
doesn't work alone. that it needs either cortotine,
PQQ, vitamin D, you know, other types of things.
If there's mitochondrial issues, you have to
address those. So it's not so, you know, it's
not so easy. And this isn't the autism pill,
you know, that a lot of patients, you know, I
have patients that haven't come back because
they told me, well, you didn't give me the autism
pill. Well, there's no autism pill. It's a work,
it's complex, and it's great to have somebody
to guide you through it. Yeah. Yeah. Yeah. Thank
you for sharing all this information. We'll definitely
be on the lookout for your research, because
I learned about Luca Horan from your first episode,
whenever I asked you what recently are you most
interested in, this was the first thing that
you mentioned. And then, obviously, the last
couple of weeks, it's hit. the news. So this
is really fantastic. Yeah, we're very lucky that
yeah, CBS, you know, picked it up and we've gotten
a lot of good press from that. Yeah. Yeah, I'll
do my best of sharing this information to you
because I think it's worthy with that low risk
high reward type of thing. Yeah. Well, Dr. Fried,
thank you for joining again and looking forward
to maybe another future interaction with you
all the time. Yeah, always happy. to beyond spread
the good word. Yeah, yeah, yeah. We appreciate
that. Have a good day and thank you so much.
All right. Take care. Thanks. Bye.